Cilta-Cel Achieves High MRD Negativity Rates in Lenalidomide-Refractory Multiple Myeloma

Updated CARTITUDE-4 trial data show cilta-cel induces deep MRD negativity in patients with lenalidomide-refractory multiple myeloma.

In the phase 3 CARTITUDE-4 trial (NCT04181827), treatment with ciltacabtagene autoleucel (cilta-cel; Carvykti) resulted in significantly higher rates of minimal residual disease (MRD) negativity compared to standard of care in patients with lenalidomide (Revlimid)-refractory multiple myeloma who had received 1 to 3 prior lines of therapy. These updated findings demonstrate the potential of cilta-cel for this patient population.

The data, which were shared during the 2025 Tandem Meeting, showed that among patients in the intention-to-treat population who received the CAR T-cell therapy (n = 208), the MRD negativity rate at the 10^-5 threshold was 62.0% vs 18.5% with SOC (n = 211; OR, 7.6; P < .0001). In the patients evaluable for MRD, the MRD negativity rate at the same threshold with cilta-cel (n = 145) was 89.0% vs 37.9% with SOC (n = 103; OR, 13.3; P < .0001).

Almost all patients who received cilta-cel and achieved MRD negativity with a sensitivity of 10^-5 were also negative at the 10^-6 threshold. In the ITT population, the MRD negativity rate at the same threshold with cilta-cel (n = 208) was 57.2% vs 9.0% with SOC (n = 103; OR, 14.9; P < .0001). In MRD-evaluable patients, the MRD negativity rate with cilta-cel (n = 139) was 85.6% vs 18.6% with SOC (n = 102; OR, 28.5; P < .0001).

High rates of overall MRD negativity were rapidly achieved with cilta-cel. Specifically, 69% of evaluable patients achieved MRD negativity at the 10^-5 threshold by day 56; this percentage rose to 86% by 6 months after infusion with cilta-cel; the respective rates in the ITT population were 48% and 60%. At the time of data cutoff, more than half of evaluable patients who received cilta-cel had sustained MRD-negative (10^-5) complete response (CR) or better of at least 12 months vs less than 10% of those given SOC.

“With this longer follow-up on the CARTITUDE-4 study, not only are we seeing that benefit [in terms of] progression-free survival [PFS], but we’re seeing some of the deeper response in that single-dose treatment [with cilta-cel] without maintenance can achieve that higher level of MRD negativity of up to 10^-6, many patients can sustain that for at least 1 year or longer, and that is translating into a corresponding much higher 30-month overall survival [OS] and PFS rates,” Yi Lin, MD, PhD, of Mayo Clinic, in Rochester, Minnesota, said in a presentation of the data.

Lin is a professor of medicine; holds joint appointments in the divisions of Hematology and Experimental Pathology and Laboratory Medicine; and is the enterprise leader of cancer regenerative medicine, biotherapeutics, and biomanufacturing at Mayo Clinic.

CARTITUDE-4 enrolled patients who were at least 18 years of age with multiple myeloma who received 1 to 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug. They were refractory to lenalidomide and had an ECOG performance status no higher than 1. They were randomized 1:1 to receive cilta-cel or SOC treatment with pomalidomide (Pomalyst), plus bortezomib and dexamethasone or daratumumab (Darzalex) plus pomalidomide and dexamethasone. Patients underwent apheresis followed by lymphodepletion and subsequent infusion with cilta-cel.

Previously, it was reported that cilta-cel significantly boosted PFS compared with SOC (HR, 0.29; 95% CI, 0.22-0.39; P < .0001).² The CAR T-cell therapy was also found to have an OS benefit vs SOC (HR, 0.55; 95% CI, 0.39-0.79; P = .0009). Overall MRD negativity was found to be higher with cilta-cel vs SOC as well, at 62.0% and 18.5%.

The current analysis looked at MRD negativity outcomes at a median follow-up of 33.6 months.¹ MRD testing was done in the bone marrow samples using next-generation sequencing at both 10^-5 and 10^-6 sensitivity thresholds. The timing of MRD assessment was from day 1 of cycle 1 for the SOC arm and from cilta-cel infusion for the cilta-cel arm.

A total of 419 patients underwent randomization; 208 comprised the cilta-cel arm and 211 comprised the SOC arm. In the cilta-cel arm, 208 patients received apheresis/bridging therapy and 176 of these patients received the CAR T-cell therapy as study treatment.

In the investigative arm, 145 and 139 patients were evaluable for MRD at the 10^-5 and 10^-6 thresholds, respectively; in the control arm, 103 and 102 were MRD evaluable at those respective thresholds. For samples to be determined to be evaluable, they needed to pass calibration and quality checks and there needed to be sufficient cells available for examination at the testing thresholds.

Additional data from the latest presentation indicated that cilta-cel increased overall MRD negativity rates at the 10^-5 threshold vs SOC across the subgroups analyzed, including those with higher risk features like older age (<65 years: OR, 7.79; 95% CI, 4.35-13.93; 65-75 years: OR, 5.86; 95% CI, 2.89-11.91), high-risk cytogenetics (high risk: OR, 12.77; 95% CI, 6.96-23.44; standard risk: OR, 3.40; 95% CI, 1.65-7.00), and tumor burden (low: OR, 7.01; 95% CI, 3.94-12.45; intermediate: OR, 5.13; 95% CI, 2.22-11.85; high: OR, 24.18 (95% CI, 4.81-121.63).

“For the patients treated on the cilta-cel arm, the MRD-negative rate and CR or greater response is quite high, at 82.1%, and only 25.2% for the SOC arm,” Lin said (OR, 12.3; P < .0001). These responses were sustained for at least 12 months in 51.7% of those on the cilta-cel arm vs 9.7% of those on the SOC arm.

“Correspondingly, we see that for the patients treated on the cilta-cel arm, those who are able to achieve that MRD negativity and CR or greater response and sustain it for 12 months or longer, the 30-month PFS rate and OS rates were significantly higher,” Lin said. In the 75 patients who had sustained MRD-negative CR or better, the 30-month PFS and OS rates were 93.2% and 97.3%, respectively.

Investigators compared MRD negativity outcomes between the CARTITUDE-4 (n = 176) and CARTITUDE-1 (NCT03548207; n = 97) trials. Lin noted higher rates of MRD negativity in the former trial vs the latter trial, which corresponded with higher rates of PFS and OS rates at 30 months. Notably, those in the former trial received 1 to 3 prior lines of therapy and those in the latter trial received 3 or more prior lines of treatment.

The overall MRD negativity rates to the 10^-5 thresholds in the CARTITUDE-4 and CARTITUDE-1 trial were 73.3% and 59.8%, respectively; to the 10^-6 threshold, these rates were 67.6% and 40.2%, respectively. In CARTITUDE-4, the respective 30-month PFS and OS rates were 68.4% and 84.3%; in CARTITUDE-1, these rates were 54.2% and 68.0%, respectively.

Biological correlates of MRD-negative CR or better were also examined in the cilta-cel arm by comparing those with an MRD-positive CR or better and those with MRD-negative CR or better. It was found that MRD-negative CR or better status was linked with enhanced immune fitness at apheresis, lower inflammatory cytokines before infusion, and higher CAR-positive T-cell expansion compared with those who had MRD-positive CR or better.

“We’re gaining some insight into the biology of the immune state of these patients that may help inform how we can continue to advance the efficacy of the therapeutic modality,” Lin concluded.

References

1. Popat R, Oriol A, Cavo M, et al. Ciltacabtagene autoleucel vs standard of care in patients with lenalidomide-refractory multiple myeloma after 1-3 lines of therapy: Minimal residual disease negativity in the phase 3 CARTITUDE-4 trial. Presented at: 2025 Transplant and Cellular Therapy Meetings; February 12-15, 2025; Honolulu, HI. Abstract 44.
2. Mateos M-V, San-Miguel J, Dhakal, et al. Overall survival (OS) with ciltacabtagene autoleucel (cilta-cel) versus standard of care (SoC) in lenalidomide (len)-refractory multiple myeloma (MM): phase 3 CARTITUDE-4 study update. Presented at: 2024 International Myeloma Society Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil. Abstract OA – 65.